Insights into molecular mechanism of action of salan titanium(IV) complex with in vitro and in vivo anticancer activity

• Published in: Journal of inorganic biochemistry Vol. 163; pp. 250 - 257
• Main Authors: Miller, Maya, Braitbard, Ori, Hochman, Jacob, Tshuva, Edit Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2016
• Subjects: Animals; Apoptosis; Cell cycle; Cell Line, Tumor; Cisplatin; Cytotoxicity mechanism; Cytotoxins - chemistry; Cytotoxins - pharmacokinetics; Cytotoxins - pharmacology; Female; Humans; In vivo; Metallodrugs; Mice; Mice, Nude; Neoplasm Proteins - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Titanium - chemistry; Titanium - pharmacokinetics; Titanium - pharmacology; Xenograft Model Antitumor Assays; In vivo; Metallodrugs; Cytotoxicity mechanism; Cisplatin; Cell cycle; Apoptosis
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.04.007

Titanium compounds, in particular, Ti(IV) based diaminobis(phenolato) “salan” complexes demonstrate high cytotoxicity towards a wide range of cancer cell lines in vitro, and still, very little is known on their mode of action. A representative salan Ti(IV) complex was tested both in vitro and in vivo on human HT-29 colorectal adenocarcinoma and A2780 ovarian carcinoma cells. Both cell lines were sensitive in vitro with A2780 demonstrating an enhanced rate of uptake and intracellular accumulation and thus an earlier response to the drug. HT-29 cells responded in vivo by impaired tumor development in nude mice. Both cell lines responded in vitro (but to a different extent) by upregulation of p53 with no apparent effect on p21 followed by cell cycle arrest, apoptosis and necrosis as demonstrated by sub-G1 cell accumulation and staining by Annexin-V and propidium iodide. Furthermore, time dependent activation of cysteine-aspartic proteases9 (caspase9) as well as some minor activation of cysteine-aspartic proteases3 (caspase3) support a direct effect on the apoptotic pathway. The differential response of the two cell lines to the salan titanium(IV) complex suggests that more than one pathway is involved in their growth regulation and thus could inhibit development of drug resistant variants. A salan Ti(IV) complex demonstrates high anticancer in vitro cytotoxicity towards human colon and ovarian cancer cells, and in vivo efficacy towards the colon cells in nude mice. Mechanistic analysis reveals induction of cell cycle arrest and apoptosis, with upregulation of p53 protein as well as time-dependent activation of caspases. [Display omitted] •A Ti(IV) compound presents high cytotoxicity with maximal effect at 48h of incubation.•The complex demonstrates in vivo efficacy with no clinical signs of toxicity.•The complex induces cell cycle arrest at G1.•Apoptosis is evident by upregulation of p53 and time-dependent activation of caspases.•A distinct behavior on two cell lines may suggest multiple mechanistic pathways.